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J Biol Chem. 2017 Jun 9;292(23):9760-9773. doi: 10.1074/jbc.M117.783605. Epub 2017 May 1.

Deficiency in the manganese efflux transporter SLC30A10 induces severe hypothyroidism in mice.

Author information

1
From the Division of Pharmacology & Toxicology, College of Pharmacy, Institute for Cellular & Molecular Biology, and Institute for Neuroscience and.
2
the Department of Microbiology and Environmental Toxicology, University of California at Santa Cruz, Santa Cruz, California 95064.
3
the Mouse Genetic Engineering Facility, Institute for Cellular & Molecular Biology, University of Texas at Austin, Austin, Texas 78712.
4
the Department of Veterinary Sciences, Michale E. Keeling Center for Comparative Medicine and Research, M. D. Anderson Cancer Center, Bastrop, Texas 78602, and.
5
the Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461.
6
From the Division of Pharmacology & Toxicology, College of Pharmacy, Institute for Cellular & Molecular Biology, and Institute for Neuroscience and som@austin.utexas.edu.

Abstract

Manganese is an essential metal that becomes toxic at elevated levels. Loss-of-function mutations in SLC30A10, a cell-surface-localized manganese efflux transporter, cause a heritable manganese metabolism disorder resulting in elevated manganese levels and parkinsonian-like movement deficits. The underlying disease mechanisms are unclear; therefore, treatment is challenging. To understand the consequences of loss of SLC30A10 function at the organism level, we generated Slc30a10 knock-out mice. During early development, knock-outs were indistinguishable from controls. Surprisingly, however, after weaning and compared with controls, knock-out mice failed to gain weight, were smaller, and died prematurely (by ∼6-8 weeks of age). At 6 weeks, manganese levels in the brain, blood, and liver of the knock-outs were ∼20-60-fold higher than controls. Unexpectedly, histological analyses revealed that the brain and liver of the knock-outs were largely unaffected, but their thyroid exhibited extensive alterations. Because hypothyroidism leads to growth defects and premature death in mice, we assayed for changes in thyroid and pituitary hormones. At 6 weeks and compared with controls, the knock-outs had markedly reduced thyroxine levels (∼50-80%) and profoundly increased thyroid-stimulating hormone levels (∼800-1000-fold), indicating that Slc30a10 knock-out mice develop hypothyroidism. Importantly, a low-manganese diet produced lower tissue manganese levels in the knock-outs and rescued the phenotype, suggesting that manganese toxicity was the underlying cause. Our unanticipated discovery highlights the importance of determining the role of thyroid dysfunction in the onset and progression of manganese-induced disease and identifies Slc30a10 knock-out mice as a new model for studying thyroid biology.

KEYWORDS:

SLC30; ZnT; cation diffusion facilitator; manganese; metal; parkinsonism; thyroid; toxicity; transporter

PMID:
28461334
PMCID:
PMC5465498
DOI:
10.1074/jbc.M117.783605
[Indexed for MEDLINE]
Free PMC Article

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